title: Inhibitor selectivity between aldo-keto reductase superfamily members AKR1B10 and AKR1B1: role of Trp112 (Trp111).
abstract: The antineoplastic target aldo-keto reductase family member 1B10 (AKR1B10) and the critical polyol pathway enzyme aldose reductase (AKR1B1) share high structural similarity. Crystal structures reported here reveal a surprising Trp112 native conformation stabilized by a specific Gln114-centered hydrogen bond network in the AKR1B10 holoenzyme, and suggest that AKR1B1 inhibitors could retain their binding affinities toward AKR1B10 by inducing Trp112 flip to result in an "AKR1B1-like" active site in AKR1B10, while selective AKR1B10 inhibitors can take advantage of the broader active site of AKR1B10 provided by the native Trp112 side-chain orientation.
authors.affiliation: School of Pharmaceutical Sciences, Centre for Cellular and Structural Biology of Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Yining
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Shangke
authors.initials: S
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhai
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Xuehua
authors.initials: X
authors.lastname: Zheng
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Hu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000074408:Aldo-Keto Reductases; D052160:Benzothiazoles / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry; D005439:Flufenamic Acid / Q000737:chemistry; D006860:Hydrogen Bonding; D048289:Imidazolidines / Q000737:chemistry; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry; D009828:Oleanolic Acid / Q000737:chemistry; D010793:Phthalazines / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012236:Rhodanine / Q000031:analogs & derivatives / Q000737:chemistry; D040681:Structural Homology, Protein; D053778:Thiazolidines / Q000737:chemistry; D014364:Tryptophan / Q000737:chemistry*
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D009281:Naphthalenes; D010793:Phthalazines; D053778:Thiazolidines; C040550:tolrestat; C067172:zopolrestat; C038131:epalrestat; D005439:Flufenamic Acid; D009828:Oleanolic Acid; D012236:Rhodanine; D014364:Tryptophan; C077139:fidarestat; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase
keywords: AKR1A1; AKR1B1; AKR1B10; Crystal structure; FLF; Inhibitor selectivity; aldehyde reductase; aldose reductase aldo–keto reductase family1 member1; aldo–keto reductase family1 member10; flufenamic acid